Phase 2a study of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of wild-type TP53 in patients with peripheral t-cell lymphoma

Abstract

Background: Peripheral T-cell lymphoma (PTCL) refers to a heterogeneous group of tumors that comprise a subset of T-cell non-Hodgkin lymphomas. PTCL-not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma are among the most common of these rare tumors. Outcomes are often poor, particularly in the setting of relapsed or refractory disease, making PTCL an ideal candidate for the assessment of a novel agent with strong biologic rationale. ALRN-6924 is a cell-penetrating stapled alpha-helical peptide designed to equipotently disrupt the interaction between the p53 tumor suppressor protein and its endogenous inhibitors, murine double minute X (MDMX) and 2 (MDM2). For TP53 wild-type (WT) tumors, pharmacological disruption of this interaction offers a means to induce p53-dependent cell cycle arrest and apoptosis, resulting in antitumor efficacy via a novel mechanism. ALRN-6924 demonstrated intriguing antitumor activity in a first-in-human phase 1 trial across a variety of tumor types (Meric-Bernstam et al., ASCO 2017, abstract #2505). Trial design: This open-label Phase 2a study (NCT02264613) will enroll up to 20 adults with relapsed or refractory PTCL, after at least one prior systemic anticancer chemotherapy. Enrolled patients must have TP53WT T-cell lymphoma (as confirmed by a central NGS testing), ECOG status of 0 or 1, and adequate organ function. Patients will receive 3.1 mg/kg ALRN-6924 as a one-hour infusion on days 1, 8, and 15 of 28-day cycles. Treatment will continue until disease progression or unacceptable toxicity. Response will be assessed according to the revised 2014 International Working Group (IWG) criteria for Lymphoma (Lugano Classification), (Cheson et al., J Clin Oncol. 2014:32:3059-3067). Primary objectives are to assess overall response rate and to further evaluate the safety and tolerability of ALRN-6924. Secondary objectives include assessment of time to response, duration of response, progression free survival, and overall survival. Pharmacodynamic biomarkers will be measured in blood and tumor samples. Recruitment is ongoing.